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Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
15 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
adequate
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

4,4’-Methylenedicyclohexanamine was examined in rats in an OECD 422 (28 -day repeated dose toxicity/reproductive toxicity) screening guideline study at doses of 15, 50 and 100 mg/kg bw/d. No abnormalities were seen in the reproductive organs of either fertile or non-fertile animals. The assessment of the integrity of the spermatogenetic cycle did not provide any evidence of impairment. Slight reproductive toxicity was noted as a decrease in implantation sites at the 50 and 100 mg/kg bw/d dose levels, the same dose at which systemic toxicity was noted in repeated dose oral toxicity studies. The control group had a number of implantation sites slightly higher than historical controls. At the lower of these two doses, there were two of 9 females with no implantation sites, which may have occurred by chance. This led to a reduction in the gestation index at 50 mg/kg bw/d, but not at 100 mg/kg bw/d. The lack of dose response causes the relevance of this parameter to be questions.

An a GLP, OECD 414 study on a structural analogue, Dimethyl-PACM, the ovaries and uterus of females were examined to determine:

number of corpora lutea,

number and distribution of dead and live fetuses,

number and distribution of early and late resorptions,

number and distribution of implantation sites.

There were no reductions or other adverse effects in fertility parameters in the OECD 414 study of DM-PACM.

This data indicates that the substance is not a reproductive toxin at doses up to 100 mg/kg bw/d


Short description of key information:
Reproductive toxicity was noted in a 28-day OECD 421/422 guideline study on 4,4’-methylenedicyclohexanamine at the 50 mg/kg bw/d dose, the same dose at which systemic toxicity was noted in repeated dose oral toxicity studies. An additional study (OECD 414)on a structural analogues (DM-PACM) did not confirm reproductive effects, and found no decrease in number of corpora lutea, implantation sites, gestation index, or resorption index

Justification for selection of Effect on fertility via oral route:
Guideline study (OECD 421/422) according to GLP

Effects on developmental toxicity

Description of key information
Developmental toxicity was noted in a guideline study on 4,4’-methylenedicyclohexanamine at the 50 mg/kg bw/d dose, the same dose at which systemic toxicity was noted in repeated dose oral toxicity studies. An OECD 414 was performed for the structural analogue DM-PACM. There were no substance-induced, dose-related influences on the gestational parameters and no signs of prenatal developmental toxicity, especially no substance induced indications of teratogenicity, up to and including the high dose-level (45 mg/kg bw/day).Hence the NOAEL was greater than 45 mg/kg bw for developmental effects in this study. 
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
45 mg/kg bw/day
Species:
rat
Quality of whole database:
adequate
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

4,4’-Methylenedicyclohexanamine was examined in an OECD 422 (28 -day repeated dose toxicity/reproductive toxicity) screening guideline study at doses of 15, 50 and 100 mg/kg bw/d. Treatment of male and female rats revealed parental toxicity at 50 and 100 mg/kg characterized by microscopic findings in various organs. Developmental toxicity was suggested as decreased number of pups at the first litter check (primarily at 100 mg/kg bw/d) and decreased viability at 4 days (primarily at 50 mg/kg bw/d). Neither of these parameters was dose-related. There was no evidence of a teratogenic effect. These effects were seen at the same dose levels where systemic toxicity was observed in repeated dose toxicity studies in adults and thus the effects may not be specific to the reproductive tract. It is likely that maternal toxicity is impacting reproductive performance.

Furthermore an OECD 414 study was performed for the structural analogue DM-PACM. There were no substance-induced, dose-related influences on the gestational parameters and no signs of prenatal developmental toxicity, especially no substance induced indications of teratogenicity, up to and including the high dose-level (45 mg/kg bw/day). At this dose only maternal toxic effects were observed. In summary and based on these study results, the substance PACM is not considered to be a teratogenic substance.


Justification for selection of Effect on developmental toxicity: via oral route:
Guideline study by GLP

Justification for classification or non-classification

This substance is not a reproductive toxicant, as only minor effects were observed in reproductive and developmental parameters at doses characterized by adult systemic toxicity. There is insufficient evidence to classify this substance as a reproductive toxicant.